Sucralfate, an aluminum salt of sucrose sulfate ester, is known to be useful in the treatment of ulcers.
Cyclodextrins are complexing agents known to form inclusion compounds with organic substances, in the solid state or in aqueous solutions. Cyclodextrins are not known to have any beneficial effect in the treatment of gastrointestinal conditions, such as ulcer.
The present inventors have discovered that, surprisingly, the combination of sucralfate and cyclodextrin affords a gastroprotective effect. Such effect is greater than the effect achieved with sucralfate alone or cyclodextrin alone. Moreover, the effect obtained with such combination is substantially greater than any possible additive effect of the activities of the components.
Data obtained by the present inventor clearly shows that the cyclodextrins of the instant invention synergize the gastroprotective effect of sucralfate.
Cyclodextrins useful in the present invention include alpha cyclodextrin, beta cyclodextrin, gamma cyclodextrin and substituted cyclodextrins, such as 2-hydroxypropyl beta cyclodextrin. Alpha cyclodextrin, beta cyclodextrin, and gamma cyclodextrin are preferred.
It is believed that the combinations of sucralfate and cyclodextrin of the present invention are complexes rather than simple mixtures.
By complex is meant an inclusion compound, inner or outer. The mechanism could involve hydrogen bonding. The present inventors have not been able to characterize the precise molecular structure. As will be shown hereinafter, the method employed in the drying step of the process used to produce the complex is a determinant of activity versus lack of activity. Freeze drying affords a substantially more active material than is obtained when the product is dried by heat (this may be indicative of an exothermic interaction). Surprisingly, air drying produces a product equivalent in activity to the sucralfate control. The fact that the process of drying is a determinant of activity versus lack of activity is consistent with complex formation, as defined herein.
The sucralfate/cyclodextrin complexes of the present invention may be prepared by a process comprising freezing, at a temperature of about -50.degree. C. to about -70.degree. C., an aqueous mixture of sucralfate and a cyclodextrin selected from the group consisting of alpha cyclodextrin, beta cyclodextrin, gamma cyclodextrin and 2-hydroxypropyl beta cyclodextrin. The sucralfate and the cyclodextrin are present in the mixture in an about equimolar ratio. The freezing is continued until the mixture is solidified. The solidified mixture is then freeze dried to produce the complex.
As noted heretofore it has been surprisingly discovered that sucralfate cyclodextrin complexes of the present invention provide a gastroprotective effect. More specifically they reduce the amount of damage to the stomach mucosa that is caused by irritants such as ethanol and the nonsteroidal antiinflammatory drugs, which are exemplified by aspirin, ibuprofen, naproxen, indomethacin, meclofenamate, piroxicam, phenylbutazone, and salicylates such as choline salicylate and choline magnesium trisalicylate.
There is no appreciation whatsoever in the prior art of the novel complexes of the instant invention, their preparation, or their gastroprotective effect.
The sucralfate/cyclodextrin complexes of the present invention are employed in a protective amount. More specifically, they are employed in an amount sufficient to reduce damage to the gastric mucosa which is caused by the aforementioned irritants.
The sucralfate/cyclodextrin complexes of the instant invention can be co-administered with the irritant or administered sometime prior to administration of the irritant. The optimum time lapse between administration of the sucralfate/cyclodextrin complex and administration of the irritant is readily determinable by one skilled in the art and will vary with the age, weight and physical condition of the subject. Most desirably, the sucralfate/cyclodextrin complex is co-administered with the irritant.
When the irritant is aspirin, the complex and the aspirin are most desirably employed in amounts such that the weight of sucralfate in the complex is about equal to the weight of the aspirin. When an NSAID, or other irritant, more irritating to the gastric mucosa than aspirin is to be administered, this weight relationship is adjusted upwardly by increasing the amount of complex employed. Consequently, when an NSAID, or other irritant, less irritating to the gastric mucosa than aspirin is to be administered, the weight relationship is adjusted downwardly by decreasing the amount of complex utilized.
Optimum respective amounts of various combinations of irritants and sucralfate/cyclodextrin in complexes of the instant invention are readily determinable by one skilled in the art, without the exercise of any inventive skill.